Insecticidal esters of chrysanthemic acid and alcohols related to 3-hydroxymethylbenzofuran

ABSTRACT

NOVEL CHRYSANTHEMIC ACID (CHRYSANTHEMUM CARBOXYLIC ACID) ESTERS OF 3-HYDROXYMETHYLBENZOFURAN AND THE CORRESPONDING SUBSTITUTED BENZOFURANS AND INSECTICIDAL COMPOSITION CONTAINING SAME.

United States Patent Office 3,816,469. Patented June 11, 1974 3,816,469INSECTICIDAL ESTERS F CHRYSANTHEMIC ACID AND ALCOHOLS RELATED TO 3-HY-DROXYMETHYLBENZOFURAN Wayne I. Fanta, Colerain, Ohio, assignor to theProcter & Gamble Company, Cincinnati, Ohio No Drawing. Filed Mar. 1,1971, Ser. No. 120,043 Int. Cl. (307d 5/42 US. Cl. 260-346.2 R 8 ClaimsABSTRACT OF THE DISCLOSURE Novel chrysanthemic acid (Chrysanthemumcarboxylic acid) esters of 3-hydroxymethylbenzofuran and thecorresponding substituted benzofurans and insecticidal compositionscontaining same.

BACKGROUND OF THE INVENTION This invention relates to novelchrysanthemic acid esters and to insecticidal compositions containingsaid esters as an essential active ingredient. Current trends in thechemical control of insects call for inherently safer materials whichdegrade very rapidly to non-toxic substances once their purpose isaccomplished. The safety of the widely used chlorinated hydrocarbons,notably DDT, is currently under question largely because of their poorbiodegradability and concomitant persistence. Accordingly, there isgreat demand for alternative broad spectrum insecticides which aresuitable for the high volume usage entailed in agriculturalapplications. At the same time it is necessary for new insecticides toexhibit a low order of toxicity to warm-blooded animals. Of the severalinsecticide classes which demonstrate low mammalian toxicity and goodbiodegradability, pyrethrum, a naturally-occurring insecticide mixture,has found wide usage. In addition to its safety advantages, this naturalmixture affords rapid knock-down and kill of a broad spectrum ofinsects; however, it is unstable to light, air, and heat, and is veryexpensive. The most active component of pyrethrum is pyrethrin I and anumber of analogous compounds have been proposed for insecticidal use.Allethrin, a widely used synthetic pyrethrum-like insecticide, whilemore stable to light and heat than pyrethrum, is nevertheless expensive,a defect which is compounded by the fact that this substance is notsynergized by the low cost synergizing agents such as piperonyl butoxidewhich are typically used in insecticidal compositions. Because ofinstability, high cost and limited supply, the use of pyrethrum andpyrethrin-like insecticides in garden and agricultural ap plications hasbeen seriously limited or precluded.

Many of these natural insecticides are esters of chrysanthemic acid, andit has long been felt that synthetic analogues of the natural compoundscould provide a better source of supply than do the natural mixtures.However, it is not possible to predict the insecticidal properties ofChrysanthemic acid esters, since even minor structural variations cancause marked changes in the insecticidal activity thereof. At the sametime, it is well known that certain insects, in time, become immune tothe insecticidal properties of various chemical agents. It

is therefore necessary to have included in the insecticidalarmamentarium various novel insecticides which can be utilized once agiven class of insects no longer responds to the parent insecticidalcomposition. For these reasons, chrysanthemic acid esters of a varietyof alcohols have been synthesized and tested as insecticides. Forexample, chrysanthemic acid esters of various furans have beenpreviously described. British Patent Specification 1,178,857, publishedJan. 21, 1970, discloses the preparation of a variety of furan andbenzofuran esters of some cyclopropanecarboxylic acids. British PatentSpecification 1,168,797, published Oct. 29, 1969, discloses somecrysanthemic acid esters of various substituted furans. The co-pendingapplication of Fanta, entitled Novel Esters of Chrysanthemic Acid, filedJan. 12, 1970, Ser.

No. 2,443, now abandoned, describes some insecticidal esters of3-coumaranol. The concurrently filed application of Morgan, entitledInsecticidal Esters of Chrysanthemic Acid and Alcohols Related to3-Hydroxymethyl-4,5,6,7- Tetrahydrobenzofuran filed Mar. 1, 1971, Ser.No. 120,042, now abandoned, relates to other insecticidal esters ofchrysanthemic acid. The co-opending application of Morgan, entitledNovel Esters of Chrysanthemic Acid and Alcohols Related to 2-Indanol,filed Mar. 16, 1970, Ser. No. 20,127, now US. Pat. 3,647,857, disclosesa variety of chrysanthemic acid esters of cyclic alcohols.

It is an object of this invention to provide novel chrysanthemic acidesters which are biodegradable, effect rapid knock-down and kill of abroad spectrum of insects, and possess low mammalian toxicity. It is afurther object of this invention to provide insecticidal compositionscontaining novel chrysanthemic acid esters of 3-hydr0xymethylbenzofuran.These and other objects are obtained by the present invention as willbecome apparent from the following disclosure.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the presentinvention are chrysanthemic acid esters of 3-hydroxymethylbenzofuran andsubstituted analogues thereof, said esters having the general formula:

wherein R is a member selected from the group consisting of hydrogen andlower alkyl, i.e., methyl, ethyl, propyl and 'butyl, and R is a memberselected from the group consisting of hydrogen, lower alkyl (e.g.,methyl, ethyl,

propyl and butyl), lower alkoxy (e.g., methoxyl, ethoxyl,.

propoxyl), phenyl and halogen (e.g., chlorine, bromine, iodine). Asynthetic scheme for the preparationof compounds having the generalformula A, above, wherein R and R are hydrogen, is outlined below.

3A -om; H O E H 1.caco c0 11 2 ---a I Cl! I zNaofi Quinoline o 0 a co st2 LiA1H H l l -1- I: III

According to the above outline, the esters of this invention encompassedby structure A are prepared by a stepwise process comprising: (1)preparing the benzofuran- 3-carboxylic acid (II) according to theprocedure described by G. Hallman and K. Higele, Ann, 662, 147 (1963);(2) reducing the acid II) to 3-hydroxymethyllbenzofuran (II) withlithium aluminum hydride; and (3) esterifying the alcohol (III) withchrysanthemoyl chloride, which in turn, is prepared by the method ofMatsui and Meguro, Agr. Biol. Chem., 28, 27 (1964).

Alternatively, the esterification step of the present in- 'vention canbe effected in other ways. The 3-hydroxymethylbenzofuran (or substitutedbenzofuran) can be heated with ehrysanthemic acid in the presence of astrong acid, in an organic solvent capable of azeotropically boilingwith water, thereby removing the Water formed in the esterification. Thebenzofuran alcohol can also be heated with a lower alkyl ester ofchrysanthemic acid in the presence of a basic catalyst such as sodiumhydroxide, potassium hydroxide, sodium alcoholate, or potassiumalcoholate, and the like, while continuously removing the lower alcoholformed through trans-esterification of the reaction system. In suchcases, the methyl, ethyl, n-propyl and iso-propyl esters ofchrysanthemic acid are suitable. In the most preferable esterification,the 3-hydroxymethylbenzofuran, or derivative thereof, is allowed toreact with the chrysanthemic acid halide, preferably at temperaturesfrom about C. to about 100 C. in an inert organic solvent, preferably inthe presence of an agent such as pyridine, triethylamine or othersuitable amine, such that the esterification proceeds with the isolationof a hydrohalic acid salt within a short period of time. For thispurpose, the chrysanthemic acid chloride is the most preferred,although. the acid bromide and the acid iodide can be employed.

Derivatives of 3-hydroxymethylbenzofuran having sub stituents R, ashereinbefore defined, on the furan ring,

and substituents R, as hereinbefore defined, on the benzene ring systemcan be prepared in a variety of ways. For example, the Hallman andHiigele reference, above, discloses the preparation of a variety ofbenzofuran acid compounds having alkyl and alkoxy groups as R and R.These acids can be reduced to the corresponding alcohols using lithiumaluminum hydride and esterified with chrysanthemoyl chloride to provideinsecticidal esters of the type herein disclosed. Other suchchrysanthernic esters of substituted benzofurans can be prepared in themanner detailed in the examples hereinafter to provide insecticidalanalogues of the parent compound A.

The compounds of this invention can exist in several isomeric andoptically isomeric forms, e.g., cis-configuration, trans-configuration,dextroand levorotatory forms of each, etc., and mixtures and racematesthereof. It is intended that the claims herein be construed to encompassall such forms and mixtures thereof. A preferred insecticidal esterherein is (i)-cis,trans-3-hydroxymethylbenzofuran chrysanthemate.

The preparation of the esters of the present invention is described inmore detail in the following examples. The examples are not intended tobe limiting, but only to demonstrate the preparation of a variety of thecompounds of this invention.

EXAMPLE I Preparation of (i)-cis,trans-chrysanthemic acid ester of 3hydroxymethylbenzofuran (Compound A; R=H, .R'=

Step 1.--3-hydroxymethylbenzofuran: To a slurry of lithium aluminumhydride (0.2 g., 6.0)(10 M), in ether (20 ml.) was addedbenzofuran-3-carboxylic acid (0.3 g., 1.9x lO- M) in diethyl ether (10ml.) over a period of 20 minutes, prepared by heating benzofuran 2,3dicarboxylic acid, copper and quinoline at 200 C., as noted in thereaction sequence described above. (The dicarboxylic acid, itself, isprepared by the base-catalyzed reaction of ethylbromoacetate andZ-hydroxyacetophenone according to the procedure of Hollman and Hagele,Ann., 662, 147, 1963.) The reaction mixture was refluxed for 16 hoursafter which it was decomposed by the addition of water (ca. 1 ml.) and15% sodium hydroxide (0.1 ml.). Filtration, solvent removal, andsublimation (pot temperature ca. C./0.25 mm.) gave 0.3 g. of whitesolid, M.P. 44-46 (3.; IR (CHCI 3600 (free OH), 3450 (H bonded OH), and870 cm.- (furan); NMR (CDCI 1- 7.4 (s, 1, OH), 5.4 (s, 2, CE OH), and2.3-3.0 (complex area, 5, aromatic protons).

Step 2.(:*:)-cis,trans-chrysanthemate of 3 -hydroxymethylbenzofuran: Amixture of chrysanthemoyl chloride (0.4 g., 2.2 10 M), preparedaccording to the procedure of Matsui and Meguro, above, pyridine (0.2g., 2.3 10- M), 3-hydroxymethylbenzofuran (0.3 g., 2.0 10 M) prepared inStep 1, above, benzene (10 ml.) was stirred at room temperature for 20hours. The reaction mixture was diluted with ether (25 ml.) and thenwashed with 1 N hydrochloric acid (10 ml.), 1 N sodium hyroxide (10ml.), and water (10 ml.). The organic phase was dried (magnesiumsulfate) and was evaporated to yield 11.4 g. of colorless liquid whichwas chromatographed on Florisil (20 ml.) with hexane. A total of 0.5 g.of liquid was obtained: homogeneous on G.L.P.C. (5' 20% SE-30 at 200 C);IR (film) 1730 cm. (ester C=O). A sample of the ester was collected bypreparative G.L.P.C. for spectral analysis: NMR (CDC1 -r 8.6 and 8.7(two singlets, ca. 6, cyclopropyl methyls), 8.4 (singlet with somesplitting, ca. 6, olefinic methyls), 4.8 (2 singlets, 2, OCH 4.7 and 5.2

(2 broad areas, 1,

and 2.3-2.9 (complex area, 5, aromatic protons). This analysiscorresponds to the ester (1-)cis,trans-3-hydroxymethylbensofuranchrysanthemate.

In the above procedure, the 2-hydroxyacetophenone used to prepare theparent dicarboxylic acid is replaced by an equivalent amount of2-hydroxy-S-methylacetophenone, 2-hydroxy-S-butylacetophenone,Z-hydroxy-S-chloroacetophenone, 2-hydroxy-5-brorno acetophenone,2-hydroxy-5-methoxyacetophenone and 2-hydroxy-5-phenylacetophenone and,following the stepwise procedure noted above, the alcohols 3hydroxymethyl 5 methylbenzofuran, 3-hydroxymethyl-S-butylbenzofuran,3-hydroxymethyl-5-chlorobenzofuran, 3-hydroXymethyl-5-bromobenzofuran,3-hydroxymethyl-S-rnethoxybenzofuran and 3-hydroxymethyl-5-phenylbenzofurau are secured, respectively. Esterification of saidalcohols with chrysanthemoyl chloride in the manner hereinbeforedescribed yields the respective insecticidal esters, e.g.,(1L)-cis,trans-3-hydroxymethyl 5- methoxybenzofuran chrysanthemate,i-cisJrans 3-hydroxymethyl-S-phenylbenzofuran chrysanthemate, i-cis,-trans-5-methylbenzofuran chrysanthemate, and the like.

EXAMPLE II Preparation of (i)-ciS,trans-chrysanthemic acid ester of2-methyl-3 hydroxymethylbenzofuran(Compound A; R=methyl, R'=H) Z-methyl3 hydroxymethyl-4,5,6,7-tetrahydrobenzofuran is prepared from2-chlorocyclohexanone and ethylacetoacetate followed by cyclization andreduction in the manner more fully described in the concurrently filedapplication of Morgan entitled Insecticidal Esters of Chrysanthemic Acidand Alcohols Related to 3-Hydroxymethyl-4,5,6,7-tetrahydrobenzofuran"filed Mar. 1, 1971, Ser. No. 120,042 now abandoned. The resultingsaturated benzofuran derivative is dehydrogenated by heating in toluenesolution with a palladium-on-carbon catalyst at about 200 C. to yield2-methyl-3-hydroxymethylbenzofuran. Refluxing this latter material withchrysanthemoyl chloride (1 :1 mole basis) in the presence of anequivalent of pyridine yields the insecticidal ester i-cis,trans 2-methyl-3-hydroxymethylbenzofuran chrysanthemate.

Following the procedure more fully described in Morgan, above, thealcohols 2-ethyl-3-hydroxymethyl-4,5,6,7- tetrahydrobenzofuran and 2methyl 3 hydroxymethyl- 5 -methyl-4,5,6,7-tetrahydrobenzofuran areprepared, re spectively. The dehydrogenation of these alcohols using apalladium-on-carbon catalyst at 200 C. yields 2-ethy1-3-hydroxymethylbenzofuran and 2 methyl-3-hydroxymethyl 5 methylbenzofuran.Esterification of these latter alcohols by refluxing with chrysanthemicacid yields the insecticidal esters (i)-cis,trans-2ethyl-3-hydroxymethylbenzofuran chrysanthemate and (1-)-cis,-trans-Z-methyl-B-hydroxymethyl 5 methylbenzofuran chrysanthemate,respectively.

According to the procedure of W. Schoetensack et al., US. Pat.3,235,566, incorporated herein by reference, is preparedethyl-Z-methyl-S-hydroxybenzofuran-3-carboxylate. Etherification of thehydroxyl group with an alkyl halide (e.g., methyl bromide, ethyl iodide,propyl bromide and the like) in the presence of base yields theS-alkoxyl derivatives of the aforementioned esters. Reduction of theester group with lithium aluminum hydride in the manner hereinbeforedetailed yields the compounds 2-methyl-3-hydroxymethyl 5methoxybenzofuran, 2- butyl-3-hydroxymethyl 5 methoxybenzofuran and 2-butyl 3 hydroxymethyl-S-butoxybenzofuran. Esterification of thesealcohols with chrysanthemoyl chloride in the hereinbefore describedmanner yields insecticidal mixtures of the respective insecticidalesters.

The compound *-)-cis,trans S-hydroxymethylbenzofuran chrysanthemate(Compound A; R=H, R'=H) prepared in Example I, was dissolved in keroseneand sprayed onto houseflies according to a modification of the proceduredescribed by C. W. Kearns and R. B. March, Soap, 19, 2, 101 (1943).Compounds B and C in Table I, i.e., (i)-cis-trarzs 2hydroxymethylbenzofuran chrysanthemate and (i) cis,trans 2hydroxymethylcoumarane chrysanthemate, were applied to houseflies in thesame fashion. The data, which represent duplicate tests using 50 fliesper test, are set forth in Table 1.

TABLE I.HOUSEFLY KNOCK-DOWN AND KILL Percent knock-down Percentmortality,

Conc., w./n. 10 min. 120 min. 24 hours A 0.1% 10 92 0.01% plus 0.1% PB 44 7 B 0.1% 3 a1 51 0.01% plus 0.1% PB-.- 6 8 10 C 0.1% 4 2 11 0.01% plus0.1% PB-.- 6 9 l0 1 Piperonyl butoxide, a common synergist used withinsecticides;

As can be seen from the foregoing, the parent compound of the class ofcompounds encompassed by this invention possesses good insecticidalproperties. Moreover, the substantially improved insecticidal activityof the compounds of this invention over the isomeric andisomeric-saturated analogues thereof is demonstrated by the data.Additionally, the compounds of the instant invention are substantiallyless toxic to mammals than are most common insecticides.

The compounds of the instant invention are similarly effective whentested against the adult mosqutio, adult stable flies, black carpetbeetle larva, webbing clothes moth larva, adult rice weevils, and adultsawtooth grain beetles.

Insecticidal compositions containing the esters of the present inventioncan be formulated and utilized as oil solutions, emulsifiableconcentrates, wettable powders, dusts, aerosols, or impregnated intowood, fabrics, etc., and provide a long lasting residual effect. Suchcompositions can include the generally employed insecticidal carriers ordiluents and auxiliary agents which are wellknown to those skilled inthe art. For example, suitable dusts can be prepared by admixing aninsecticidal amount of the compounds of the invention with dryfree-flowing powders such as clay, bentonite, fullers earth,diatomaceous earth, pyrophyllite, attapulgite, calcium carbonate, chalkor the like. The active compounds of the invention normally comprise upto about by weight, of such dust formulations. An amount of about 0.01%to 10%, by weight, is preferred and is suitable for most applica tions.Likewise, suspensions or dispersions of the insecticidal compounds in anon-solvent. such as water, can be suitably employed for the treatmentof foliage. Also suitably employed are solutions of the insecticides ofthis invention in oil which is emulsified in Water. Examples of oilsolvents include hydrocarbons such as benzene and toluene, halogenatedhydrocarbons such as chlorobenzene, chloroform, fiuorotrichloromethaneand dichlorodifluoromethane, and commercial mixtures of hydrocarbonssuch as the common Stoddard solvents, petroleum ethers, and the like.

Aerosols can be prepared by dissolving an insecticidal amounts of thecompounds of this invention in a highly volatile liquid carrier such astrifluorochloromethane, nitromethane, dichlorodifluoroethane and thelike, or by dissolving such compounds in a less volatile solvent, suchas benzene or kerosene, and admixing the resulting solution with ahighly volatile liquid aerosol carrier such as thepolyfluorohydrocarbons commonly used as aerosol propellants.

In the above-noted suspensions and aerosol compositions, about 0.005% toabout 50%, by Weight, more preferably about 0.005% to about 10%, byweight, of the chrysanthemate esters of this invention are suitable foruse. The novel compounds of the invention are useful for controlling avariety of insects. Accordingly, a method aspect of the presentinvention comprises combating insects by applying to insects or to aninsect habitat one or more of novel compounds of the invention.

In some instances the esters of this invention are employed incombination with a synergistic agent, for example, piperonyl butoxide,the n-octylsulfoxide of isosafrole, 13 butoxy-B-thiocyanodiethyl etherand the like. These agents as well as the hereinbefore recited carriersand diluents and mixtures thereof are encompassed by the expressioninsecticidal carrier. Some exemplary insecticidal compositionscontaining the compounds of this invention are as follows.

Insecticidal Composition I An insecticidal composition suitable forgeneral use in the home and garden is prepared as follows:

Percent (Wt.): Ingredient 1.0 :)-cis,trans-3-hydroxymethylbenzofuranchrysanthemate. 2.0 Triton X-100 emulsifier.

Balance Water.

Application of the above suspension to flies, oat bugs and Germancockroaches as a spray or by brush application eflectively controlsthese insects. In the above composition, the(i)-cis-trans-3-hydroxymethylbenzofuran chrysanthemate is replaced by anequivalent amount of (i) cis,trans-2-ethyl-3-hydroxymethylbenzofuranchrys anthemate, (i) cz's,trans-2-methyl-3-hydroxymethyl-S-chlorobenzofuran chrysanthemate and (i) cis,trans-3-hydroxymethyl-5-propoxybenzofuran chrysanthemate and equivalent resultsare secured in that these insect pests are killed.

Insecticidal Composition II Percent (wt.): Ingredient(i)-cis,trans-3-hydroxymethylbenzofuran chrysanthemate. 0.5 Sulfur.Balance Chalk.

The insecticidal dust described above is suitable for use on all mannerof shrubs and plants and is preferably applied out-of-doors.

In the above composition, the concentration of (i)- cis,trans3-hydroxymethylbenzofuran chrysanthemate is increased to about byweight, of the total composition. The resulting insecticidal dustprovides superior knock-down and kill of stinging insects such as wasps,bees and the like and is suitable for clearing areas of infestation bysuch insects.

Insecticidal Composition III Percent (wt.): Ingredient 0.005(i)-cis,trans-S-hydroxymethylbenzofuran chrysanthemate. 5% Polyethyleneglycol (mol.

wt. range 600l0,000).

Balance Propellant gas.*

50 50 mixture of trifluorochloromethane and dichlorodifluoroethune,containing aboue 10 p.p.m nitromethane.

The above composition is suitable for application to domestic animalsfor control of gnats, flies, fleas and the like.

In the above aerosol insecticidal composition the concentration ofbenzofuran chrysanthemate is increased to about 1.5% and the resultingcomposition is suitable for use with domestic farm animals such as cows,sheep and the like to control black flies, horse flies, blow flies, andother insect pests.

In the above compositions the )-cz's,tmns-3-hydroxymethylbenzofuranchrysanthemate is replaced by an equivalent amount of(1-)cis,trans-3-hydroxymethyl-5- methylbenzofuran chrysanthemate,(i)-cis,trans-2-methyl-3-hydroxyrnethyl-5-methylbenzofuranchrysanthemate, (d: -cis,trans-3-hydroxyrnethyl-5-phenylbenzofuranchrysanthemate, (i)-cis,trans-3-hydroXy-methyl 5 methoxybenzofuranchrysanthemate, and (:)-cis,trans-2-methyl- 3-hydroxymethylbenzofuranchrysanthemate, respectively, and equivalent insecticidal compositionsare secured.

What is claimed is:

1. A compound of the formula CH: CH;

wherein R is a member selected from the group consisting of hydrogen,methyl, ethyl, propyl, and butyl and wherein R is a member selected fromthe group consisting of hydrogen, methyl, ethyl, propyl, butyl,methoxyl, ethoxyl, propoxyl, phenyl, chlorine, bromine and iodine.

2. A compound in accordance with claim 1 which is (i)-cis,tmns 3hydroxymethylbenzofuran chrysanthemate.

3. A compound in accordance with claim 1 which is (i)-cis,trans 2 methyl3 hydroxymethylbenzofuran chrysanthemate.

4. A compound in accordance with claim 1 which is(i)-cis,trans-3-hydroxymethyl 5 methoxybenzofuran chrysanthemate.

5. A compound in accordance with claim 1 which is (:)-cis,trans- 3hydroxymethyl 5 phenylbenzofuran chrysanthemate.

6. A compound in accordance with claim 1 which is (i)-cis,trans- 3-hydroxymethyl 5 methylbenzofuran chrysanthemate.

7. A compound in accordance with claim 1 which is i)-cis,trans-2-ethyl-3 hydroxymethylbenzofuran chrysanthemate.

8. A compound in accordance with claim 1 which is (i)-cis,tra.'zs 2methyl 3 hydroxymethyl-S-methylbenzofuran chrysanthemate.

References Cited UNITED STATES PATENTS 3,567,740 3/1971 Matsui 26034743,465,007 9/1969 Elliot 260347.4

JOHN D. RANDOLPH, Primary Examiner B. DENTZ, Assistant Examiner US. Cl.X.R.

